Common patient‐reported sources of cancer‐related distress in adults with cancer: A systematic review

Abstract Background Cancer‐related distress (CRD) is widely experienced by people with cancer and is associated with poor outcomes. CRD screening is a recommended practice; however, CRD remains under‐treated due to limited resources targeting unique sources (problems) contributing to CRD. Understanding which sources of CRD are most commonly reported will allow allocation of resources including equipping healthcare providers for intervention. Methods We conducted a systematic review to describe the frequency of patient‐reported sources of CRD and to identify relationships with CRD severity, demographics, and clinical characteristics. We included empirical studies that screened adults with cancer using the NCCN or similar problem list. Most and least common sources of CRD were identified using weighted proportions computed across studies. Relationships between sources of CRD and CRD severity, demographics, and clinical characteristics were summarized narratively. Results Forty‐eight studies were included. The most frequent sources of CRD were worry (55%), fatigue (54%), fears (45%), sadness (44%), pain (41%), and sleep disturbance (40%). Having enough food (0%), substance abuse (3%), childbearing ability (5%), fevers (5%), and spiritual concerns (5%) were infrequently reported. Sources of CRD were related to CRD severity, sex, age, race, marital status, income, education, rurality, treatment type, cancer grade, performance status, and timing of screening. Conclusions Sources of CRD were most frequently emotional and physical, and resources should be targeted to these sources. Relationships between sources of CRD and demographic and clinical variables may suggest profiles of patient subgroups that share similar sources of CRD. Further investigation is necessary to direct intervention development and testing.


| BACKGROUND
Nearly everyone with cancer experiences cancer-related distress (CRD) to some degree.CRD is defined by the National Comprehensive Cancer Network (NCCN) as: a multifactorial unpleasant experience of a psychological (i.e., cognitive, behavioral, emotional), social, spiritual, and/or physical nature that may interfere with one's ability to cope effectively with cancer, its physical symptoms, and its treatment.][6][7][8][9] Screening for CRD has been a point of emphasis since its proposal as a standard of care in 1999, 10 but, to date, has focused nearly exclusively on CRD severity.Identification of 'actionable' CRD (CRD requiring intervention) is determined by patient-reported severity that meets or exceeds a clinical cut-off, for example, ≥4 on the 0-10 NCCN Distress Thermometer (DT).2][13] Moreover, reluctance to report CRD and accept referrals has been reported if there is a perception that needed resources are limited or unavailable, 12,13 disclosure could be stigmatizing, or could result in unwanted referral for mental/psychosocial healthcare. 12Moving focus from CRD severity to sources of CRD could have utility in identifying risk and improving management of CRD.For the purposes of this paper, "sources of CRD" refers to the specific problems or concerns that contribute to the experience of CRD, such as those identified on the NCCN Distress Thermometer Problem List (PL).
Some organizations attempt to simplify CRD screening by using depression or anxiety measures but fail to capture other sources of CRD. 14 CRD screening measures should provide people with cancer opportunity to report sources of CRD, allowing healthcare professionals to provide targeted interventions at the time of screening, and/or timely referral for management of specific sources of CRD, (e.g., physical or emotional symptoms, relationship problems, unmet practical needs, existential concerns).
While capturing the source(s) of CRD is critical to providing appropriate intervention, the variety of CRD sources listed on commonly used measures like the PL or the Canadian Problem Checklist (CPC) have been identified as a barrier to CRD screening and management. 15ealthcare and community organizations may not have resources needed to offer interventions for the wide range of CRD concerns people may report.Since its introduction, there have been several iterations of the PL, including 46 international adaptations or translations, which have increased the number and variety of sources of CRD from 19 to upwards of 35.International versions of the PL include additions or modifications to items reflecting differences in cultures and healthcare systems, such as access to care, transportation, insurance/financial systems, etc. 16 Empirical evidence regarding which sources of CRD to include on screening PLs has been limited to a few single site studies or quality improvement projects, which limits generalizability of findings.A study attempting to refine the UK version of the PL added sources to the physical, practical, and spiritual domains based on sources of CRD which were most frequently reported in a sample of 395 patients. 17Using a larger sample (n = 11,155 medical records), guideline authors 18 reference a conference presentation citing common concerns in emotional (72.5%), physical (67.5%), and practical domains (43.1%). 19requency of general domains of CRD is helpful information yet precludes the ability of healthcare providers to be prepared to intervene for specific concerns and increases reliance on referrals for continued triage.Finally, an Australian study aiming to alleviate the burden of CRD assessment used principal component analysis to reduce the number of items on the PL.The authors proposed a two-item PL consisting of the main components, worry and depression. 15Such a PL would likely fail to capture CRD from sources other than anxiety or depression. 14ith limited aggregate data to rely on, sources of CRD appearing on PLs are largely based upon lower-level evidence and expert consensus among panel members. 1,20To our knowledge, this is the first systematic examination of global evidence regarding frequency of reported sources of CRD.
The purpose of this systematic review was to identify the most (and least) common patient-reported sources of CRD and associated characteristics in adults with cancer.Our aims were to: (1) describe which patient-reported sources of CRD are most and least frequently reported in the literature globally and by continent, (2) examine reported relationships between sources of CRD and actionable levels of CRD severity; and (3) examine reported relationships between sources of CRD and clinical and demographic characteristics.Understanding reported sources of CRD can help guide allocation of resources toward interventions for frequently reported sources of CRD and/or those shown to predict actionable levels of CRD severity.Knowledge of associations between sources of CRD and demographic and clinical characteristics can aid in the identification of individuals at risk for actionable levels of CRD and allow clinicians to intervene proactively.

| Inclusion and exclusion criteria
Empirical studies of adults (≥18 years of age), diagnosed with cancer, screened for CRD with the PL or similar measure, and reporting the specified sources of CRD were included.We excluded studies which focused solely on specific subtypes of distress (symptom distress, moral distress, etc.) which differ conceptually from CRD.We also excluded qualitative studies, as they did not provide information about frequency of CRD sources or quantify associations between sources of CRD, actionable CRD, and demographics or clinical characteristics.Articles which collected limited PL data from select domains were also excluded.

| Data collection process
The lead author screened titles, abstracts, and full text articles with at least one other member of the research team.Disagreements were discussed among the coauthors until consensus was reached.Data extraction included study characteristics (study design, setting, and location; sample size, cancer diagnosis, stage, treatment type and status), CRD screening information (CRD screening measure, PL version, cut-off used, proportion of sample reporting actionable CRD, proportion of the sample reporting each source of CRD), and significant reported relationships between sources of CRD and actionable CRD severity, demographics, and clinical variables.Baseline data was extracted from longitudinal studies.All data were extracted by the lead author into a spreadsheet created for this review.Data were reviewed and verified for accuracy by at least one other study team member.Disagreements were resolved through additional review and discussion with coauthors until consensus was reached.

| Data analysis
We computed a weighted proportion for each source of CRD to evaluate its relative frequency across studies.For each CRD source, we computed the number of persons endorsing the concern (multiplying the percentage reported by the study's sample size, if necessary), then summed the number endorsing across studies and divided by the pooled sample size.We analyzed findings globally, then repeated the analyses at the continent level.Sources of CRD were organized into (1) standard sources of CRD according to the NCCN PL, version 2.2021, and (2) additional sources of CRD found on modified PLs and other measures.

| Aims 2 and 3
Statistically significant relationships between CRD domains or individual sources of CRD and actionable levels of CRD severity, demographics, and clinical characteristics were analyzed narratively.We organized relationships by CRD domain and summarized findings with respect to the direction of the relationship.

| Quality appraisal
The Mixed Methods Appraisal Tool (MMAT) was used to assess quality of included studies. 21We rated each study on five criteria based on type of study design.Studies meeting at least four of the five criteria, and achieving a rating of ≥80%, were considered high quality.Ratings of 40%-60% were considered moderate, and ratings below 40% were considered poor quality.We did not exclude articles based on quality reporting for aim 1, which focused on descriptive data.Findings from studies of low quality were excluded for aims 2 and 3, as risk of bias jeopardizes validity of the relationships that were subject to statistical tests.

| Study selection
A total of 2324 articles were screened for eligibility, 2321 yielded from search results after removing duplicates and three articles identified through hand searching reference lists.Forty-eight articles of unique studies met inclusion criteria and were included in this review (see PRISMA diagram, Figure 1).A table summarizing data from all included studies is presented in Table 1.

| Study characteristics
Most included studies were quantitative descriptive studies (n = 46), with one randomized controlled trial and one mixed methods study.Most were cross-sectional (n = 42).Forty-four studies were conducted among people with solid tumor cancers, and four studies included people with hematologic malignancies only.More than half of the studies included participants representing multiple cancer types (n = 29).Across studies, participants were mainly female (55%), married (72%), and White (79%).Studies were mainly conducted outside of the United States (n = 37) in outpatient clinic settings (n = 34).The NCCN DT/ PL was the most common measure used (n = 40), with eight studies using modified versions or alternate measures (e.g., CPC).Study characteristics are presented in Table 2.

| Quality appraisal
The majority of included studies were high quality (n = 33).Thirteen studies were rated moderate quality, and two studies were rated low quality. 46,60Quality ratings for each of the studies are reported in Table 3.

3.4
| Aim 1-Most and least common patient-reported sources The 10 most reported sources of CRD, based on the NCCN PL version 2.2021, 2 were worry (55%), fatigue
3.6 | Aim 3-Sources of CRD and demographic and clinical characteristics 3.6.1 | Sources of CRD and demographics Emotional concerns were related to age, sex, marital status, income, education, and rurality in 10 studies.In general, emotional concerns were negatively correlated with age, 36,56 income, 67 and education. 36,67Women were found to report concerns from emotional, 27,39,43,51,62 and psychosocial 29 domains more frequently than men.Among specific emotional concerns, worry and fears were more frequently reported by people with lower incomes, 59 people living in rural areas, 47 and people with lower/informal education. 36,67Nervousness was more frequently reported by partnered individuals, 59 people with lower incomes, 59 and people with lower/informal education. 36hysical concerns were related to age, sex, race/ethnicity, income, and rurality in nine studies.Reporting fatigue as a source of CRD was negatively related to age and income. 59Women reported physical concerns 27,43,51,62 more frequently than men with exception of changes in urination, 39 and sexual concerns. 29,39,51Physical concerns were more frequently reported among the ethnic majority in Malaysia 36 and among African Americans (specifically, changes in urination, memory/concentration, fertility, and sexual problems). 38Physical concerns about pain, mouth sores, and nausea were more frequently reported by people living in rural areas. 47ractical concerns were related to age, sex, race/ethnicity, marital status, rurality, and education in seven studies.Practical concerns were more frequently reported by young adults, 56 men, 43,51 African Americans, 38 and single individuals. 29Among specific concerns, insurance and transportation were more frequently reported by African Americans 38 and people living in rural

Sources of CRD associated with clinical characteristics
Concerns significantly associated with actionable CRD were: • Health insurance (OR 7.6) • Depression (OR 6.9) • Worry (OR 4.4) • Fear (OR 3.9)

Sources of CRD associated with clinical characteristics
• Greater number of endorsements is associated with actionable CRD • Actionable CRD related to emotional (p < 0.001), practical (p < 0.0001), family (p = 0.003), and physical (p < 0.0001) concerns decreased over time • Decrease in actionable CRD over time differed between men and women related to physical (p = 0.046) and family (p = 0.048) concerns • Males reported more practical, concerns than women at baseline, but women reported more practical concerns than men at mid and end study points • Women reported more concerns, particularly emotional and physical concerns than men • Patients reported fewer physical concerns over time areas. 47Concerns about work/school more frequently reported by African Americans. 38Concerns about childcare were more frequently reported by people with secondary education. 36amily concerns were related to age and sex in five studies, with more frequent reports by young adults 56 and women. 27,36,39,51Spiritual concerns were related to sex and race/ethnicity in two studies, 27,38 with spiritual concerns being reported more frequently by women 56 and African Americans. 38 3.6.2 | Sources of CRD and clinical characteristics Emotional concerns were related to treatment type and insurance in three studies. Eotional concerns were reported more frequently by people receiving chemotherapy, 59 especially when not preceded by surgery or radiation therapy.36 Specific concerns of sadness, fears, and nervousness were reported more frequently by people receiving chemotherapy, 59 while worry was reported less frequently by people who had surgery and those with private health insurance versus government-provided insurance.36,67 Physical concerns were related to treatment type, cancer grade, and time of screening in four studies.Pain and fatigue were more likely to be reported by people receiving chemotherapy, 59 while physical concerns were reported less frequently by people who had surgery.36 Physical concerns were reported more frequently by people with highgrade cancers 51,62 and those who received CRD screening prior to seeing the oncologist.36 Practical concerns were related to treatment type, cancer grade, and performance status in four studies. Prctical concerns were more frequently reported by people with high-grade cancers 51,62 and poorer performance status.50 Concerns about childcare were more frequently reported by people receiving treatments other than chemotherapy.53 No significant relationships were reported between family or spiritual concerns and clinical characteristics across studies.    psychosocial domain has 13 concerns: burden to others, worry about family/friends, talking with family, talking with medical team, family conflict, changes in appearance; alcohol/drugs, smoking, coping, sexuality, spirituality, treatment decisions and sleep disturbance.c Data not included in analysis for aim 2 and aim 3.
4.1 | Most/least frequent sources of CRD Findings demonstrate common reported sources of CRD with relative consistency across continents.More than 40% of people across studies reported worry, fatigue, fears, sadness, pain, and sleep disturbance as sources of CRD.Clinicians can anticipate that people with cancer are likely to report these common sources as contributing to their CRD and prepare available interventions in advance.Cancer care organizations should consider allocating resources toward implementing interventions known to be beneficial for management of common sources of CRD, such as physical activity, guided imagery or mindfulness for management of CRD from fatigue and sleep disturbance. 702][73] Providing interventions at the time of screening may reduce reliance on referrals to social workers, health psychologists, and/or other specialists, which people with cancer frequently decline or fail to follow-up. 12,13,74wenty-seven of the forty sources of CRD on the PL (version 1.2021) were reported by less than 25% of pooled samples, with ≤5% reporting concern about lack of food, substance use, spiritual problems, fevers, and childbearing ability.Depression, often used as a proxy measure for CRD, was reported by less than 25% of the pooled sample and only appeared among the top 10 reported sources of CRD in studies conducted in Asian countries.Low reporting of depression suggests that organizations using depression measures, such as the Patient Health Questionnaire, 75 to screen for CRD risk failing to identify a majority of people with CRD from other sources.This is consistent with research demonstrating that the NCCN DT/PL was able to detect CRD missed by measures of depression or anxiety 14 and strengthens guidance recommending use of CRD-specific screening tools. 71ur review invites consideration to refine the sources of CRD that are included in standard screening measures.The NCCN PL recently underwent major revision, eliminating many physical concerns, adding sources of CRD to practical and spiritual concerns, modifying the family domain to a more inclusive social domain, and relocating some sources of CRD to different domains. 20While the most highly reported physical concerns of fatigue, pain, and sleep disturbance remain, a number of the retained physical concerns had low frequency of reporting in the current review, for example, substance abuse (3%) and sexual concerns (12%).Conversely, three physical concerns removed from the NCCN PL were reported by at least 25% of the pooled sample in the current review, for example, getting around (34%), dry/itchy skin (30%), tingling in hands/feet (26%).Having enough food, though not reported as a source of CRD across included studies, was retained on the updated PL.Finally, six spiritual concerns were added, addressing aspects of spirituality broadly from dietary considerations to concern about death and dying.

NR
In our review, spiritual concerns (as a single item) were reported by only 5% of pooled samples.The addition of new sources of CRD in this domain may reveal higher endorsement in future studies.Some CRD sources such as access to food, childcare, substance use, and financial toxicity merit inclusion for even low levels of endorsement to facilitate treatment adherence and mitigate potential harms. 76,77PLs using a set of common core sources of CRD augmented with CRD sources of significant consequence or important for select patient subgroups (e.g., diagnosis or therapy-specific) may enhance usefulness in high-risk groups while minimizing screening burden for others.with memory or concentration, housing issues, financial concerns, and/or domestic partner concerns could be considered at increased risk for actionable CRD.Moving concerns with low association with actionable CRD, such as having enough food and substance use, to a supplemental module could be considered, particularly if the intent is to assess for the presence of the condition (identifying unmet need), rather than distress from it.9][80] For example, a person may use substances, such as use of cannabinoids for management of appetite, nausea, or pain, but not be distressed by it.

| CRD sources related to clinical and demographic characteristics
Differences in reported sources of CRD and demographics, specifically age, sex, marital status, income, rurality, and education were identified.In general, being male, older, and partnered reduced frequency of reporting emotional, physical, family, and practical concerns.Younger people and people with lower education and/or income appeared to report more emotional and practical concerns.Although the majority of study samples were White and urban-dwelling, our findings suggest that race/ethnicity and rurality may contribute to differences in reported sources of CRD.Relationships were also identified between reported sources of CRD and clinical characteristics including cancer grade, treatment type, insurance, performance status, and timing of screening.Higher grade cancers were associated with more physical and practical concerns.Receiving chemotherapy was associated with more emotional and physical concerns, but fewer practical concerns (childcare) than other treatment types.Having private health insurance was associated with lower endorsement of worry as a source of CRD.Poor performance status was associated with greater endorsement of practical concerns.Physical concerns were more frequently reported by people who were screened for CRD before seeing their oncologist.
While our synthesis summarized evidence regarding bivariate relationships, it is likely that relationships among sources of CRD and demographic and clinical characteristics are far more complex.For example, Giese-Davis and colleagues 29 observed age and gender to interact in their relationship with sources of CRD, finding that

Statistical analysis is appropriate
Troy et al. 65 100% ▲ ▲ ▲ ▲ ▲ VanHoose et al.People with cancer have reported multiple cooccurring, interrelated sources of CRD.Physical and emotional effects of cancer and treatment (inflammation, activated hypothalamic procedures, etc.) are thought to contribute to clustering sources contributing to CRD, such as pain, depression, and fatigue. 81,82acobs and colleagues identified CRD problem clusters, including fears and tension, weight changes and eating, and physical fitness and fatigue. 58CRD symptom clusters were identified among head & neck cancer survivors relating to adjustment (appearance, breathing, and worry), rurality (speech, getting around, and illness), and others. 83Many of the most reported sources of CRD are also found within common symptom clusters, such as co-occurring pain, fatigue, and sleep disturbance. 84,85Further research is needed to evaluate the contribution of symptom clusters as sources of CRD and the effect of CRD on the experience of multiple cooccurring symptoms.
A more sophisticated analysis, which takes complexities of relationships into account, such as latent class modeling, may be helpful for identifying common characteristics of people who report similar patterns in sources of CRD.For example, a young Asian woman with breast cancer will likely have a different CRD profile than an older African American male with prostate cancer. 86,87Current practice relies on risk stratification for intervention based on CRD severity using the CRD severity exceeding a cut-off score (usually DT ≥4), 1 with people reporting sub-clinical CRD (severity of three or less) may not receive any follow-up, regardless of the sources of CRD reported.Our findings indicate that some sources of CRD may be more distressing than others and may be appropriate for intervention regardless of reported CRD severity.Research has demonstrated that lack of appropriate aftercare is the most significant barrier to CRD screening program implementation and screening with immediate intervention/resources is more effective than screening alone. 88,89Greater understanding of common sources of CRD and, and possibly CRD profiles, could facilitate an improved risk-stratified approach to CRD screening and management by allowing to be proactive in offering targeted psychosocial interventions for the common sources of CRD.Greater understanding of sources of CRD can enhance research in CRD management by clarifying targets for intervention development.

| Strengths and limitations
This review has a number of strengths.First, this review represents a novel line of inquiry.To our knowledge, no other review has synthesized the available evidence about common patient-reported sources of CRD, associations between sources of CRD and actionable CRD, or associations between sources of CRD and demographic or clinical characteristics.This analysis is critical for understanding the overall picture of patient-reported sources of CRD not attainable from single studies or quality improvement projects.Second, we synthesized evidence from literature on a global scale.The majority of studies reporting sources of CRD (n = 37) were conducted outside the United States.
We present results at the continent-level to assist researchers and clinicians in transferring the knowledge to their respective contexts.Third, weighting the data by sample size during analysis reduced risk for data from smaller studies to overexert influence on the results.Finally, we employed a rigorous methodology for screening, data extraction, data analysis, and quality assessment.Findings of this review should be interpreted in context of some limitations.It is possible that our review failed to capture every study that reported common sources of CRD.Further, we limited our review to studies reported in English; thus, our findings reported by continent may exclude relevant studies published in other languages.T A B L E 5 (Continued)  Several studies had to be excluded due to incomplete reporting of sources of CRD which may result in over-or under-representation in our synthesis.Several studies reported only statistically significant associations between demographic and/or clinical characteristics, potentially underrepresenting null findings.
In conclusion, this review found commonly reported sources of CRD, specifically worry, fatigue, sleep disturbance, fears, and sadness, that were generally consistent across global locations.In the clinical setting, healthcare providers can anticipate that many of the people in their care will experiencing CRD from one or more of these sources.Resources should be allocated toward implementation of interventions for these concerns which can be administered by providers at the time of screening and point of care.Moreover, results can be used to refine screening tools, informing a core set of CRD sources for all persons with cancer and supplemental items for specific diagnoses, treatment approaches, or risk categories.Finally, results of this review can inform future research to identify people at risk for CRD by examining shared patterns in reported sources of CRD and associated demographic and clinical characteristics and directing development of targeted interventions.

Associations between actionable CRD and sources of CRD Sources of CRD associated with demographic characteristics Sources of CRD associated with clinical characteristics
• Greater number of endorsements was associated with actionable CRD in emotional (p < 0.001), family (p = 0.014), physical (p = 0.039), and spiritual (p = 0.046) domains • Endorsement of practical concerns was not associated with actionable CRD Number of reported sources in any domain of CRD did not significantly differ by sex Number of reported sources in any domain of CRD did not differ significantly by diagnosis • Actionable CRD was related to reporting physical (93%) and emotional (74%) sources of CRD NR NR Greater number of endorsements is associated with actionable CRD in all CPC domains (p < 0.001) Women reported more concerns than men overall (p < 0.001), and in specific domains of emotional (p < 0.001), social (p < 0.001), spiritual (p < 0.001), and informational (p = 0.008) NR NR NR NR • Endorsement of psychosocial concerns was associated with actionable CRD at baseline (r = 0.386, p < 0.001) and 12 months • (r = 0.266, p < 0.001) • Age (younger) and sex (female) predicted greater number of psychosocial endorsements (p < 0.001; had significantly higher odds of reporting actionable CRD (OR = 2.402, p < 0.001; OR 1.163, p = 0.004) NR NR Authors observed people with actionable CRD reported proportionally more concerns on the PL than those with non-actionable CRD.T A B L E 1 (Continued) (Continues)
aBaseline n/data used for longitudinal studies.

4.2 | CRD sources related to actionable levels of CRD severity
Characteristics of included studies (n = 48).
Table of overall reported sources of CRD (NCCN PL version 2.2021; most to least reported).
References of included studies, listed by continent.Note: Tables showing comprehensive results for continent-level analyses are available from the first author by request.
T A B L E 5